CROI: Anti-HBV drug entecavir also active against HIV and promotes antiretroviral resistance

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The hepatitis B drug entecavir (Baraclude) demonstrates activity against HIV and selects for mutations that confer resistance to certain antiretroviral medications, according to a study presented Wednesday at the Fourteenth Conference on Retroviruses and Opportunistic Infections in Los Angeles.

Two agents currently approved for the treatment of hepatitis B virus (HBV) infection – lamivudine (3TC; Epivir-HBV) and adefovir (Hepsera) also demonstrate activity against HIV. Further, two approved anti-HIV drugs -- emtricitabine (Emtriva) and tenofovir (Viread) – are also active against HBV, and are in clinical trials for this indication.

This leaves few antiviral drugs that are believed to be active only against HBV, namely entecavir and telbivudine (Sebivo); Tyzeka), which was just approved by the European Medicines Agency last week. (Interferon works in a different way, by stimulating the body’s immune response rather than acting directly against HBV.)

Glossary

hepatitis B virus (HBV)

The hepatitis B virus can be spread through sexual contact, sharing of contaminated needles and syringes, needlestick injuries and during childbirth. Hepatitis B infection may be either short-lived and rapidly cleared in less than six months by the immune system (acute infection) or lifelong (chronic). The infection can lead to serious illnesses such as cirrhosis and liver cancer. A vaccine is available to prevent the infection.

replication

The process of viral multiplication or reproduction. Viruses cannot replicate without the machinery and metabolism of cells (human cells, in the case of HIV), which is why viruses infect cells.

antiviral

A drug that acts against a virus or viruses.

polymerase chain reaction (PCR)

A method of amplifying fragments of genetic material so that they can be detected. Some viral load tests are based on this method.

concentration (of a drug)

The level of a drug in the blood or other body fluid or tissue.

Such agents are important because some HIV/HBV co-infected individuals do not yet require HIV treatment. Using a single dually-active agent such as lamivudine for HBV treatment is likely to select for drug-resistant HIV strains, as it would be equivalent to using antiretroviral monotherapy.

The study presented this week, however, suggests that entecavir is in fact active against HIV and encourages the development of an HIV mutation known as M184V, which confers resistance not only to entecavir, but also to lamivudine and emtricitabine. Both drugs are commonly used as “backbone” nucleoside reverse transcriptase inhibitors (NRTIs) in antiretroviral therapy regimens; lamivudine is a component of the Combivir, Trizivir and Epzicom fixed-dose combination pills, whilst emtricitabine is included in the Truvada and Atripla pills.

Presenter Dr Chloe Thio from Johns Hopkins University reported on three cases in which HIV/HBV co-infected patients not receiving antiretroviral therapy experienced at least a 1-log decline in HIV viral load after starting entecavir for hepatitis B treatment. HIV RNA levels later rebounded in two of these individuals.

To explore this effect, Dr Thio and colleagues performed a laboratory analysis in which HIV-infected CD4 cells were exposed to increasing concentrations of antiviral drugs. To assess the emergence of resistance mutations, they obtained and cloned HIV isolates from the patient described in the first case report at several time points while on entecavir monotherapy. In addition, they used PCR testing to determine whether HIV replication was affected by exposure to entecavir.

They found that entecavir potently inhibited HIV replication with a 50% inhibitory concentration (IC50) between 0.1 and 1 nM, which is below the plasma concentration typically achieved with a normal dose of entecavir for hepatitis B treatment. PCR tests showed that entecavir inhibited the activity of the HIV reverse transcriptase enzyme, thereby slowing viral replication.

The analysis of the HIV samples from the co-infected patient showed that the M184V mutation accumulated over time. At baseline, none of the HIV clones harboured the mutation, compared with 61% at four months and 96% at six months after starting entecavir.

The researchers concluded that entecavir is a potent -- but partial -- inhibitor of HIV replication in vivo and in vitro, and that it can select for the M184V mutation, which confers high-level resistance to entecavir.

During discussion of the presentation, a representative from entecavir manufacturer Bristol-Myers Squibb said that the company had extensively tested the drug over ten years, and did not see activity against HIV. Dr Thio replied that her study used a more precise assay that was not yet available when entecavir was in development.

What should HIV/HBV co-infected patients do now?

Dr Thio and colleagues concluded that these results have important implications for the treatment of hepatitis B in HIV-positive individuals. “Entecavir should not be used in HIV/HBV co-infected individuals not on a fully suppressive HIV regimen without careful consideration of other options,” they wrote.

After these case reports came to light in the month preceding the Retrovirus conference, Health Canada issued warning about the use of entecavir alone in HIV/HBV co-infected patients.

In addition, the US Food and Drug Administration and Bristol-Myers Squibb notified healthcare providers that the entecavir product label is being revised to reflect the new information. The label originally stated that “entecavir has no clinically relevant HIV activity.”

“Healthcare professionals are advised that when considering therapy with Baraclude in an HIV/HBV co-infected patient not receiving HAART, the risk of developing HIV resistance cannot be excluded based on current information,” according to Bristol-Myers Squibb’s recent letter to health professionals.

As noted, there are few antiviral agents active against HBV but not HIV. With entecavir out of the picture, only the newest approved anti-HBV drug -- telbivudine – remains. Given the latest entecavir results, it should be carefully tested for even minor anti-HIV activity using the most sensitive assays.

Another option is to treat HIV/HBV co-infected patients with multiple anti-HBV drugs, thus slowing the emergence of resistance to a single agent. Finally, reconsideration could be given to starting such individuals on antiretroviral therapy along with anti-HBV therapy, with regular monitoring for hepatotoxicity since patients who require hepatitis B treatment may have advanced liver disease.

References

McMahon M et al. The anti-hepatitis B drug entecavir inhibits HIV-1 replication and selects HIV-1 variants resistant to antiretroviral drugs Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 136LB, 2007.